N-(1-Oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine, generically known as Valsartan, is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the AT1 receptor subtype. Valsartan is used for the treatment of hypertension and is marketed as the free acid under the name DIOVAN®.
Ciba-Geigy has disclosed Valsartan and its pharmaceutically acceptable salts for the first time in U.S. Pat. No. 5,399,578.
U.S. Pat. No. 5,399,578 describes two different processes for the preparation of Valsartan. One of these processes involves the reaction of 4-bromomethyl-2′-cyanobiphenyl (II) with L-valine methyl ester, followed by treatment with valeryl chloride to produce 2-amino-N-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-N-valeryl propionate (IV). Compound (IV) is treated with tri-n-butyl tin azide to give N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′biphenyl]-4-yl]methyl-L-valine methyl ester (V), which is then hydrolyzed under alkaline condition to give finally Valsartan. The process is shown in Scheme-I below:

This patent also describes a variant of the above method with using 2-cyano-4-formylbiphenyl instead of 4-bromomethyl-2′-cyanobiphenyl (II).
The disadvantage of the above-mentioned methods is the use of toxic tributyl tin azide to build the tetrazol ring and high demands on safety in order to prevent an explosion due to the formation of hydrogen azide during the reaction.
According to U.S. Pat. No. 5,399,578, Valsartan can also be prepared by reaction of 4-bromomethyl-2′-(1-triphenylmethyltetrazol-5-yl)biphenyl (VI) with L-valine benzyl ester to produce N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]-methyl]-L-valine benzyl ester (VII), followed by treatment with valeryl chloride to produce N-(1-oxopentyl)-N-[[2′-(1-triphenylmethyltetrazol-5-yl)[1,1′-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (VIII). Compound (VIII) is deprotected under acidic conditions to produce N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (IX), which is then hydrogenated in presence of Pd/C catalyst to give finally Valsartan. The process is shown in scheme II, below:

A major disadvantage of the above method is the fact that all the intermediates except the compound (IX) are oily substances, which can not be crystallized. The final product is therefore, strongly contaminated with undesired compounds and requires repeated crystallization, resulting in a significant loss of yield. Further the use of expensive hydrogenating catalysts like palladium on charcoal for debenzylation is not viable for the commercial point of view.
WO 2004/101534 describes a variation to the above process of preparation of Valsartan, which involves isolation of N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methy]valine benzylester (VII) in the form of hydrochloride salt. The hydrochloride salt is further converted to Valsartan.
This process also suffers with major disadvantage of low yield and low purity of N-[[2′-(1-triphenylmethyltetrazoi-5-yl)biphenyl-4-yl]methy]valine benzylester (VII), which is the key intermediate in the preparation of Valsartan. The reason for such low yield is not described in any of the prior art. We have now found that the reason for the low yield is that the triphenylmethyltetrazol group is highly unstable towards the strong acidic conditions (hydrochloric acid) and undergoes hydrolysis to generate undesired impurities, which get carried forward as impurities in Valsartan (I). Removal of these impurities in the final stage is often proved to be difficult and requires repeated crystallizations, which finally results in the low yield of compound of Formula I.
In the process of the present invention, we have now found that, N-[[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]valine methyl ester (X) can be purified as its crystalline oxalic acid addition salt (Xa), and can be used as such to produce Valsartan of high purity and yield.